Ulinastatin alleviates rhabdomyolysis-induced acute kidney injury  by suppressing inflammation and apoptosis via inhibiting TLR4/ NF-κB signaling pathway

Abstract Acute kidney injury (AKI) is an important complication of rhabdomyolysis(RM),but there is lack of effective treatments.Ulinastatin (UTI) is a broad-spectrum serine protease inhibitor isolated and purified from human urine with strong anti-inflammatory and cytoprotective actions.The aim of this research was to investigate the effect and potential mechanism of UTI on RM-induced AKI(RM-AKI). We established RM-induced AKI model and myoglobin (Mb) stimulated- NRK-52E cells model.In vivo, twenty-four rats were randomly divided into three groups(n = 8):control, RM-AKI and RM-AKI + UTI. In vitro,the NRK-52E cells were divided into six groups according to the different treatment method.Mb stimulated- NRK-52E cells were treated with UTI or si-TLR4 transfection to characterize the mechanisms of UTI in RM-AKI. Indicators of the kidney injury, cell viability, cell cycle, oxidative stress, inflammation,apoptosis and TLR4/NF-κB signaling pathway were assessed.In vivo and in vitro,UTI significantly decreased the expression of TLR4 and p65.In vivo, UTI significantly improved renal function,reduced inflammatory reaction and kidney injury.In vitro,UTI protected NRK-52E cells from Mb stimulation by suppressing cells cytotoxicity, cell cycle inhibition, overproduction of ROS, inflammation and apoptosis. Additionally, UTI played a protective role by down regulating the TLR4 expression.The results indicate that UTI alleviates RM-AKI by suppressing the inflammatory response and apoptosis via inhibiting TLR4/NF-κB signaling pathway.Our study provides a new mechanism for the protective effect of UTI on RM-AKI.